Diabetes is one of the most common global non-communicable diseases. It is the fourth or fifth leading cause of death in most developed countries and there is substantial evidence that it is epidemic in many developing and newly industrialized nations. Type-2 diabetes constitutes about 85 to 95% of all diabetes in developed countries and accounts for an even higher percentage in developing countries. To date about 200 million people have been diagnosed with diabetes. The disease prevalence is expected to grow excessively in the coming years due to the ageing population and the increasing number of people that are over-weight.
Complications from diabetes, such as coronary artery and peripheral vascular disease, stroke, diabetic neuropathy, amputations, renal failure and blindness are resulting in increasing disability and reduced life expectancy, thus causing spiraling health costs in society. This makes diabetes one of the most challenging health problems of the 21st century.
In addition to diabetes, the condition of impaired glucose tolerance (IGT) also constitutes a major public health problem, both because of its association with diabetes incidence and its own association with an increased risk of the development of cardiovascular diseases. IGT is recognized as being a stage in the transition to diabetes. About 350 million people have been diagnosed with IGT. Individuals with IGT are at high risk of progressing to type-2 diabetes, with 70% of IGT suffers expected to develop diabetes.
The aforementioned complications from diabetes are typically exacerbated when the blood glucose levels of diabetes sufferers are outside what is considered to be a healthy or normal range. For this reason, blood glucose of diabetic patients is measured regularly to detect hypo- and hyperglycemia and to monitor treatment in order to maintain such normal glucose levels. Continuous tracking of blood glucose level is important to be able to accurately dose glucose level controlling medication, e.g. insulin and maintain normal physiological levels of glucose in the blood.
The goal of maintaining normal physiological levels of glucose has led to the development of many glucose sensing devices suitable for measuring glucose levels both in vivo and in vitro. Most of these sensors are based on electrochemical principles and employ enzymes for molecular recognition. Glucose oxidase for example is used as a glucose sensitive enzyme layer to measure glucose concentration in most test strips.
Traditional glucose monitoring methods to be performed by the patient typically rely on the patient drawing a drop of blood, e.g. by a finger prick, and applying the drop to a test strip. Such methods have the drawback that they are often perceived as uncomfortable, in particular when several daily readings are required, as this can cause soreness of finger tissue due to repetitive pricking. Such distress can lead to non-compliance of the patient with the required monitoring regime, which increases the risk of the patient suffering undesirable blood glucose values. There is therefore a long-felt need to provide blood glucose measurement systems that are perceived as minimally invasive by the patients.
Medtronic MiniMed has developed a new continuous sensor based on the glucose oxidase reaction. The Guardian RT (“Real Time”) received FDA approval in August 2005. The system records as many as 864 glucose readings during a three-day period, after which the sensor is replaced. The sensor wirelessly transmits readings to a monitor every 5 minutes. The patient reads the glucose value on the monitor's screen and decides on an insulin dose. Patients can set alarms to warn them of dangerously high or low levels, and all the information can be downloaded to a computer and displayed as reports and charts. The system needs to be calibrated twice a day using a standard blood glucose meter.
Abbott Laboratories, which acquired TheraSense and its FreeStyle product line in 2004, is developing the FreeStyle™ Navigator. This system consists of a biochemical sensor that is inserted under the skin, a transmitter that snaps onto the sensor, and a pager-sized receiver. Information is transmitted wirelessly once every minute. The display shows glucose readings, arrows indicating the trend in the readings, and the rate of change in the trend. The FDA is currently considering pre-market approval for the product in the US.
The DexCom corporation is developing the STS Sensor, which also consists of a sensor inserted under the skin, a wireless transmitter, and a receiver that displays continuous glucose readings and trend information. It also has high and low alerts. The sensor will need to be replaced every three days. The system is currently also under FDA review.
Another approach to a minimally invasive method brings the interstitial fluids out of the tissue so that it can be tested. A technique called reverse iontophoresis applies a weak electrical current to the skin, and pulls interstitial fluids out through the skin and into a measuring device. The Cygnus GlucoWatch G2™ Biographer, which was introduced in 2001, uses this method. The device must be calibrated with a standard blood glucose meter when the sensor is changed, which is every 13 hours.
The SpectRx company is developing a technology that uses a laser to create microscopic holes through the outer layer of dead skin. The interstitial fluid then flows out of the holes into a patch that contains a standard glucose sensor. The results are displayed on a wireless meter.
An alternative approach to measure glucose levels in the interstitial fluids uses microdialysis to extract the interstitial fluids from the skin. A thin catheter is inserted into the subcutaneous fatty layer under the skin. A perfusion fluid inside the catheter is in continuous contact with the interstitial fluid, and pulls glucose into the catheter. The perfusion fluid is then pumped out into a measuring device.
Yet another approach relies on the fact that glucose either absorbs or scatters (near-) infrared light differently than other constituents of the skin and subcutaneous tissue, such that measuring e.g. the scattering effect of a beam of IR projected onto the skin could be used to calculate blood glucose levels.
A different kind of light, fluorescence, may also provide a means of glucose detection and measurement. GluMetrics is another US based company that has developed a glucose sensing technology called GluGlow™. This technology relies on boronic-acid based compounds that glow in the presence of glucose. The company's first application has been announced to be a catheter tipped with GluGlow, that can be used to monitor hospitalized patients.
The university of Maryland has developed a glucose sensing contact lens, which contains boronic acid-based fluoroprobes that exhibit a reduction in their fluorescence intensity upon the covalent binding of D-glucose:
An example of such a lens has been disclosed by R. Badugu et al. in Current Opinion in Biotechnology, 16, 2005, pages 100-107. It was reported that the presence of the boronic acid group on the ortho, meta or para-position of the phenyl group bound to the nitrogen made it possible to accurately determine glucose levels in tear fluid by a reduction of the fluorescence intensity from these molecules due to changes in their electron distribution that were induced by the binding of the glucose. It is known per se that the glucose levels in tear fluid reliably follow blood glucose levels with a time lag of approximately 30 minutes. However, a drawback of this lens is that it requires a light source to be directed at the lens when placed in the eye of the patient, which can be perceived as uncomfortable. Moreover, it requires active participation from the patient to monitor glucose levels, which therefore does not avoid the risk of non-compliance with the required monitoring regime.